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Inducible costimulator protein (ICOS) controls T helper cell subset polarization after virus and parasite infection.

Kopf M, Coyle AJ, Schmitz N, Barner M, Oxenius A, Gallimore A, Gutierrez-Ramos JC, Bachmann MF - J. Exp. Med. (2000)

Bottom Line: Blocking of ICOS alone had a limited but significant capacity to downregulate Th subset development.In contrast, cytotoxic T lymphocyte (CTL) responses, which are regulated to a minor and major extent by CD28 after LCMV and VSV infection, respectively, remained unaffected by blocking ICOS.Together, our results demonstrate that ICOS regulates both CD28-dependent and CD28-independent CD4(+) subset (Th1 and Th2) responses but not CTL responses in vivo.

View Article: PubMed Central - PubMed

Affiliation: Basel Institute for Immunology, 4005 Basel, Switzerland. kopf@bii.ch

ABSTRACT
It has been shown that certain pathogens can trigger efficient T cell responses in the absence of CD28, a key costimulatory receptor expressed on resting T cells. Inducible costimulator protein (ICOS) is an inducible costimulator structurally and functionally related to CD28. Here, we show that in the absence of CD28 both T helper cell type 1 (Th1) and Th2 responses were impaired but not abrogated after infection with lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), and the nematode Nippostrongylus brasiliensis. Inhibition of ICOS in CD28-deficient mice further reduced Th1/Th2 polarization. Blocking of ICOS alone had a limited but significant capacity to downregulate Th subset development. In contrast, cytotoxic T lymphocyte (CTL) responses, which are regulated to a minor and major extent by CD28 after LCMV and VSV infection, respectively, remained unaffected by blocking ICOS. Together, our results demonstrate that ICOS regulates both CD28-dependent and CD28-independent CD4(+) subset (Th1 and Th2) responses but not CTL responses in vivo.

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Blocking ICOS does not affect frequencies of LCMV-specific CTLs. CD28−/− mice (right) and C57BL/6 control mice (left) were infected with LCMV and treated with ICOS-Ig or control IgG1. Spleen cells were isolated 12 d after infection, and specific T cells were stained using H-2Db tetramers pulsed with peptide p33.
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Figure 6: Blocking ICOS does not affect frequencies of LCMV-specific CTLs. CD28−/− mice (right) and C57BL/6 control mice (left) were infected with LCMV and treated with ICOS-Ig or control IgG1. Spleen cells were isolated 12 d after infection, and specific T cells were stained using H-2Db tetramers pulsed with peptide p33.

Mentions: It has been reported that LCMV induces an efficient CTL response in the absence of CD28 12. Therefore, the role of ICOS in the regulation of CTL responses against LCMV was assessed next. C57BL/6 and CD28-deficient mice were infected locally in the footpads with LCMV and treated repeatedly every 2 d with ICOS-Fc or control hIgG1. LCMV induces an immunopathological footpad swelling reaction upon local injection of live virus 21. This swelling reaction is mediated exclusively by CD8+ T cells in the early phase of an immune response, and therefore serves as an excellent in vivo read-out for CTL activity 22. LCMV-induced footpad swelling reaction was clearly impaired in the CD28-deficient mice. However, blocking ICOS showed no effect on footpad size in either control or CD28-deficient mice, indicating that it was not significantly involved in the induction of this CD8+ T cell–mediated immunopathology (Fig. 5 A). In agreement with these results, the lytic activity of LCMV-specific CTLs, as determined by classical 51Cr-release assay, was slightly reduced in CD28-deficient mice, but remained unaffected in control and CD28-deficient mice treated with ICOS-Fc (Fig. 5 B). To directly assess the frequency of LCMV-specific CTLs by flow cytometry, we stained spleen cells from infected mice with CD8 and MHC class I tetramers loaded with specific peptide 13. Consistent with the lytic activity, CD28-deficient mice showed a frequency of specific CD8+ T cells that was reduced by ∼25% compared with control mice, whereas ICOS in the presence and absence of CD28 appeared to play no significant role in the regulation of CTL proliferation after infection with LCMV (Fig. 6).


Inducible costimulator protein (ICOS) controls T helper cell subset polarization after virus and parasite infection.

Kopf M, Coyle AJ, Schmitz N, Barner M, Oxenius A, Gallimore A, Gutierrez-Ramos JC, Bachmann MF - J. Exp. Med. (2000)

Blocking ICOS does not affect frequencies of LCMV-specific CTLs. CD28−/− mice (right) and C57BL/6 control mice (left) were infected with LCMV and treated with ICOS-Ig or control IgG1. Spleen cells were isolated 12 d after infection, and specific T cells were stained using H-2Db tetramers pulsed with peptide p33.
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Related In: Results  -  Collection

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Figure 6: Blocking ICOS does not affect frequencies of LCMV-specific CTLs. CD28−/− mice (right) and C57BL/6 control mice (left) were infected with LCMV and treated with ICOS-Ig or control IgG1. Spleen cells were isolated 12 d after infection, and specific T cells were stained using H-2Db tetramers pulsed with peptide p33.
Mentions: It has been reported that LCMV induces an efficient CTL response in the absence of CD28 12. Therefore, the role of ICOS in the regulation of CTL responses against LCMV was assessed next. C57BL/6 and CD28-deficient mice were infected locally in the footpads with LCMV and treated repeatedly every 2 d with ICOS-Fc or control hIgG1. LCMV induces an immunopathological footpad swelling reaction upon local injection of live virus 21. This swelling reaction is mediated exclusively by CD8+ T cells in the early phase of an immune response, and therefore serves as an excellent in vivo read-out for CTL activity 22. LCMV-induced footpad swelling reaction was clearly impaired in the CD28-deficient mice. However, blocking ICOS showed no effect on footpad size in either control or CD28-deficient mice, indicating that it was not significantly involved in the induction of this CD8+ T cell–mediated immunopathology (Fig. 5 A). In agreement with these results, the lytic activity of LCMV-specific CTLs, as determined by classical 51Cr-release assay, was slightly reduced in CD28-deficient mice, but remained unaffected in control and CD28-deficient mice treated with ICOS-Fc (Fig. 5 B). To directly assess the frequency of LCMV-specific CTLs by flow cytometry, we stained spleen cells from infected mice with CD8 and MHC class I tetramers loaded with specific peptide 13. Consistent with the lytic activity, CD28-deficient mice showed a frequency of specific CD8+ T cells that was reduced by ∼25% compared with control mice, whereas ICOS in the presence and absence of CD28 appeared to play no significant role in the regulation of CTL proliferation after infection with LCMV (Fig. 6).

Bottom Line: Blocking of ICOS alone had a limited but significant capacity to downregulate Th subset development.In contrast, cytotoxic T lymphocyte (CTL) responses, which are regulated to a minor and major extent by CD28 after LCMV and VSV infection, respectively, remained unaffected by blocking ICOS.Together, our results demonstrate that ICOS regulates both CD28-dependent and CD28-independent CD4(+) subset (Th1 and Th2) responses but not CTL responses in vivo.

View Article: PubMed Central - PubMed

Affiliation: Basel Institute for Immunology, 4005 Basel, Switzerland. kopf@bii.ch

ABSTRACT
It has been shown that certain pathogens can trigger efficient T cell responses in the absence of CD28, a key costimulatory receptor expressed on resting T cells. Inducible costimulator protein (ICOS) is an inducible costimulator structurally and functionally related to CD28. Here, we show that in the absence of CD28 both T helper cell type 1 (Th1) and Th2 responses were impaired but not abrogated after infection with lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), and the nematode Nippostrongylus brasiliensis. Inhibition of ICOS in CD28-deficient mice further reduced Th1/Th2 polarization. Blocking of ICOS alone had a limited but significant capacity to downregulate Th subset development. In contrast, cytotoxic T lymphocyte (CTL) responses, which are regulated to a minor and major extent by CD28 after LCMV and VSV infection, respectively, remained unaffected by blocking ICOS. Together, our results demonstrate that ICOS regulates both CD28-dependent and CD28-independent CD4(+) subset (Th1 and Th2) responses but not CTL responses in vivo.

Show MeSH
Related in: MedlinePlus